The global aim of this project, proposed under the R21 exploratory/developmental mechanism, is to examine the interplay between genetic factors for substance dependence and the age at onset of drinking or smoking, while advancing our understanding of the role of these variables in addiction through descriptive, and quasi- experimental, epidemiological studies. Early onsets of alcohol and tobacco use are strong, potentially modifiable risk factors for addiction, and it is in the best interest of public health to understand the key modifiable pathways by which their influence is exerted. The genetic aspect of this application is motivated by neurobiological studies in animal models that suggest adolescence as a critical period of vulnerability for the development of substance dependence. We will take advantage of existing data from a genetically informative case-control sample of over 4,000 subjects to test the hypothesis that age at onset of substance use moderates the effects of some addiction susceptibility genes in conferring liability to addiction. The epidemiological aspect of this application is motivated by recent studies from our group, which have documented secular trends in alcohol dependence, particularly among women, that correspond closely to historical changes in age-at-onset of drinking. Because these changes occurred during periods of changing drinking-age laws, we propose to investigate the possible role of minimum legal alcohol purchase ages (MLPA's) as a risk factor for alcohol and drug dependence in later adulthood. We will also investigate secular trends in lifetime and current dependence on other drugs of abuse. These epidemiological studies will use existing data from the National Longitudinal Alcohol Epidemiologic Survey and the National Epidemiological Survey on Alcohol and Related Conditions will be examined. Each survey has data on over 40,000 subjects. The comparability of the two surveys, spaced ten years apart, allows for detailed analyses of secular trends, and the availability of state identifiers makes it possible to use state-level drinking age policies as a 'natural experiment'that may have influenced long-term alcohol and drug use patterns through early alcohol use pathways. The coordinated study of potential gene-environment interactions and environmental main effects together will shed further light on the etiological link between these risk factors and addiction, and may help identify sub-groups of individuals, defined by demographic group or genetic risk level, who would be most likely to benefit from interventions aimed at delaying substance use. PUBLIC HEALTH RELEVANCE: Substance use disorders are among the top contributors to preventable early mortality in the United States today. Early onset of substance use is a strong and potentially malleable risk factor for common addictions. This project aims to shed further light on the potential benefits and limitations of delaying substance use by examining both gene-environment interactions and direct environmental influences in relation to the association between early substance use and substance use disorders.